期刊
BLOOD
卷 115, 期 21, 页码 4206-4216出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-11-251751
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类别
资金
- National Institutes of Health [5K99GM080097, CA66996, CA36167, DK50654, R01 CA130876-01A1]
- Office of Science, Office of Basic Energy Sciences, US Department of Energy [DE-AC02-05CH11231]
- Leukemia & Lymphoma Society
Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I-BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFR alpha (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors. (Blood. 2010; 115(21): 4206-4216)
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